1. Field of the Invention
The present invention relates to antimicrobials, and, more particularly, to antimicrobials for the control of Candida albicans, wood decay fungi, and Pseudomonas aeruginosa. 
2. Description of the Related Art
Microorganisms are among the most diverse groupings of organisms on earth and include viruses, bacteria, and fungi. Microorganisms are ubiquitous and can be found in almost every habitat. In addition to the many natural processes of microbes, these microscopic organisms have been exploited by humans for a wide variety of beneficial uses. Despite these beneficial uses, many types of microorganisms are pathogenic to humans and cause increasing numbers of deaths annually.
Fungi, for example, are a large group of eukaryotic organisms that include yeasts, molds, and mushrooms. Fungi can be found in almost every habitat including aquatic, high salt, and high radiation environments. Although approximately 100,000 species of fungi have been identified to date, it is estimated that there are as many as 1.5 million more species yet to be characterized.
Although many species of fungi have beneficial uses including as a direct or indirect food source, an agent for the production of antibiotics, the subject of basic scientific research, and a biological agent to control other unwanted species, fungi also cause millions of dollars in damage every year. Several species of fungi are pathogens that cause serious and even deadly infections in humans, while other species destroy food sources or stores. Still other species have the capacity to digest man-made materials, thereby causing serious structural damage to buildings.
In humans, the fungi Candida is the primary fungal pathogen as well as the fourth most common class of microbes causing bloodstream infections. In particular, the Candida albicans (“C. albicans”) yeast species represents 53.2 percent of Candida infections in the U.S. According to the Surveillance and Control of Pathogens of Epidemiologic Importance surveillance system of nosocomial bloodstream infections in U.S. hospitals, the mortality rate associated with nosocomial candidemia is 40 percent. In addition, yeast infections present a threat to immunocompromised HIV patients, since 60 percent of this population carries C. albicans. Despite the serious problems associated with fungal infections, there are only four classes of antifungal agents available for treatment, represented by azoles, polyenes, pyrimidines, and echinocandins. In general, these antifungal agents cause growth inhibition or cell death primarily by affecting the cell wall or membrane. The azole antifungals, such as fluconazole, are the most widely used antifungal drugs; they inhibit ergosterol synthesis in fungi and consequently cause the accumulation of toxic intermediates. Polyenes kill fungi by forming a channel through the membrane which leads to the leakage of intracellular components. The pyrimidines interfere with RNA synthesis and DNA replication in fungi. Echinocandins are a new class of antifungal drugs compared to the other three classes; they target the 1,3-β glucan synthase involved in the synthesis of cell wall components.
Although these antifungal agents exhibit a remarkable ability to combat fungal infections, fungal drug resistance has developed rapidly in the last two decades. One recent study has shown that 33 percent of late-stage AIDS patients carried drug-resistant C. albicans strains. Multiple factors contribute to C. albicans drug resistance, including the extrusion of toxic compounds through efflux pumps, the reduction of the permeability of membrane to drug molecules, the modification of drug targets, titration of the drug by the overexpression of drug-binding proteins, the degradation or modification of drug molecules, and substitution of the enzymes involved in the target pathway. For example, the ATP-binding cassette (ABC) transporters CDR1/CDR2 and the major facilitator MDR1 promote resistance by extruding drugs from the intracellular space. Besides the activation of efflux pumps among azole-resistant strains, mutations in ERG11 (encoding the azole target-14α-lanosterol demethylase) have been found to significantly reduce the affinity of drug molecules to their target proteins. In addition to the adaptive strategies exhibited by individual cells, C. albicans can also develop resistance by forming multicellular sessile communities known as biofilms on solid surfaces. Several studies have suggested that C. albicans biofilms are up to 1,000 times more resistant than their planktonic counterparts to antimicrobials such as fluconazole. These adaptive mechanisms have resulted in a significant increase in the number and severity of multidrug-resistant fungal infections and has exacerbated the demand for new antifungal drugs.
In addition to causing potentially deadly infections in humans, fungal growth can cause serious financial loss. Growth of fungi on lumber, for example, can result in costly structural damage, loss of building materials, and detrimental effects on indoor air quality. Wood damage by fungal growth can occur at several stages. Species can populate live trees, grow during transport and storage of cut timber, or populate finished structural elements. Rot caused by fungi—including both white rot and brown rot—results from the degradation of lignin and cellulose, the two components of wood. Three fungal organisms, Gloeophyllum trabeum, Chaetomium globosum, and Trametes versicolor, have been identified as the most serious offending species. The growth of fungi on indoor, outdoor, and stored building materials can result in significant costs to suppliers and home owners. Additionally, indoor growth of fungi can result in the release of toxins, leading to an unfavorable detrimental impact on the air quality of homes and offices.
Various techniques have been employed to prevent fungal growth in building materials. For example, wood is commonly treated with preserving chemicals such as zinc borate, flavanoids, and dimethyloldihydroxyethyleneurea. Wood is also treated with heat, pressure, and drying techniques to enhance decomposition resistance. However, the disposal of treated wood and general leaching of preservatives has caused serious environmental concerns. Additionally, heat and pressure methods used to prevent fungal growth may reduce the strength properties of some woods. As a result, there is still a need for antifungal treatment methods that are innocuous to the environment and will not affect the strength of building materials.
Since recent studies have shown that brominated furanones, produced as secondary metabolites by the marine red macro alga Delisea pulchra, have remarkable activities against the colonization of both prokaryotes and eukaryotes, they are promising reagents for fungal control. Several natural and synthetic furanones have been shown to control a variety of microbial phenotypes such as the growth of Gram-positive bacteria and multicellular behaviors of Gram-negative bacteria. For example, the natural furanone (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone has been found to repress genes associated with chemotaxis, motility and flagellar synthesis in E. coli. This furanone has also been shown to have an inhibitory effect on the growth Bacillus subtilis and was found to induce genes associated with stress responses, fatty acid biosynthesis, lichenan degradation, transport, and metabolism in that organism. However, the inhibitory effects of many natural and synthetic brominated furanones on C. albicans or wood decay fungi have not yet been studied.
Bacterial infections also present serious problems to humans. In the U.S. alone, the treatment of nosocomial infections costs approximately USD$ 11 billion annually. Roughly half of these infections are related to medical devices that are implanted in patients for different lengths of duration. Device-associated infections are chronic with considerable morbidity and mortality. According to the Centers for Disease Control and Prevention, there are more than one million such cases annually in the U.S., which result in more than 45,000 deaths. It is well documented that the microbes causing device-associated infections are attached to surfaces and grow in biofilms, which are highly hydrated structures comprised of a polysaccharide matrix secreted by the bound microbes. Biofilm cells are up to 1000 times more tolerant to antimicrobials and disinfectants compared to their free-swimming counterparts. As a result, antibiotics can only eliminate planktonic cells and the symptoms reoccur upon the release of cells from biofilms.
Biofilms cause a wide range of problems for environment, industry, and public health-related issues. Consequences of biofilm formation include infections from medical devices such as intravenous catheters, joint prostheses, cardiac pacemakers, prosthetic heart valves, peritoneal dialysis catheters and cerebrospinal fluid shunts, as well as billions of dollars worth of damage in industry due to increased corrosion of metallic equipment. Thus, controlling biofilm formation is critically important for a broad range of concerns for both medical and industrial communities.
With the important roles that biofilms play in device-associated infractions and the unsatisfactory efficacy of antibiotics in treating such infections, it is important to develop new methods to control biofilm formation. Previous discoveries have shown that brominated furanones exhibit activity against the colonization of bacteria, but there is a continuing need to discover and develop brominated furanones that are effective against biofilm formation.